Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transferrin is reported to be a major lipopolysaccharide binding protein of human plasma, at least in vitro. By use of the limulus-amebocyte-lysate test the influence of transferrin on endotoxicity was studied. In the absence of any other protein human iron-free transferrin was able to strongly enhance endotoxicity in a concentration-dependent manner. Similar results were obtained when transferrin was added to primarily heat-inactivated plasma. Even in this assay the endotoxin recovery increased when transferrin was exogenously added. On the other hand, transferrin inhibited endotoxicity when inactivation of the plasma samples was performed after the addition of endotoxin and transferrin. These results lead to the conclusion that transferrin in fact interacts with lipopolysaccharide in a biologically important manner. In order to achieve neutralization of endotoxin, however, other plasma constituents are needed. The hypothetical function of transferrin is possibly a disaggregation of lipopolysaccharide micelles, following the interaction between the two molecules. The present data should justify further studies in order to clarify a possible benefit of the substitution of transferrin during gram-negative sepsis.
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PMID:Demonstration of an interaction between transferrin and lipopolysaccharide--an in vitro study. 180 33

Infection occurring in patients suffering from severe trauma or burns often leads to hypotension, disseminated intravascular coagulation, multiorgan failure, and death. These latter pathophysiologic changes often are associated with Gram-negative sepsis and endotoxemia. Substantial progress has been made in understanding the effector mechanisms for endotoxin (LPS) action with the recognition of the importance of LPS-inducible products of cells of monocytic lineage in mediating LPS-induced injury. Here we will review recent evidence that supports a model for monocyte/macrophage activation by LPS that involves a plasma protein known as lipopolysaccharide binding protein (LBP) and the monocyte differentiation antigen, CD14.
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PMID:A new model of macrophage stimulation by bacterial lipopolysaccharide. 225 81

The primary structure of lipopolysaccharide binding protein (LBP), a trace plasma protein that binds to the lipid A moiety of bacterial lipopolysaccharides (LPSs), was deduced by sequencing cloned complementary DNA. LBP shares sequence identity with another LPS binding protein found in granulocytes, bactericidal/permeability-increasing protein, and with cholesterol ester transport protein of the plasma. LBP may control the response to LPS under physiologic conditions by forming high-affinity complexes with LPS that bind to monocytes and macrophages, which then secrete tumor necrosis factor. The identification of this pathway for LPS-induced monocyte stimulation may aid in the development of treatments for diseases in which Gram-negative sepsis or endotoxemia are involved.
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PMID:Structure and function of lipopolysaccharide binding protein. 240 37

Bactericidal/permeability-increasing protein (BPI) is a natural constituent of human neutrophils. Recombinant BPI has been shown to bind to bacterial lipopolysaccharide (LPS), and to neutralize the ability of LPS to stimulate inflammatory cells in vitro and in vivo. BPI shares sequence homology and immunocrossreactivity with another endogenous LPS binding protein, lipopolysaccharide binding protein (LBP). Despite the homology, these proteins have opposite effects on LPS. LBP mediates cell activation by low, otherwise nonstimulatory concentrations, while BPI neutralizes LPS bioactivity. Exogenous LPS binding proteins in the form of monoclonal antibodies have been developed with the goal of generating antiendotoxin therapeutics to treat gram-negative sepsis and related syndromes. Here we show that LPS-binding and neutralizing properties of BPI compare favorably with two monoclonal antibodies tested, HA-1A and XMMEN-OE5. BPI also competes effectively with LBP for LPS. Thus, BPI may represent an endogenous LPS-regulatory molecule suitable for use as a potent antiendotoxin therapeutic.
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PMID:Regulation of the response to bacterial lipopolysaccharide by endogenous and exogenous lipopolysaccharide binding proteins. 750 40

Mononuclear phagocytes, stimulated by bacterial lipopolysaccharide (LPS), have been implicated in the activation of coagulation in sepsis and endotoxemia. In monocytes LPS induces the synthesis of tissue factor (TF) which, assembled with factor VII, initiates the blood coagulation cascades. In this study we investigated the mechanism of LPS recognition by monocytes, and the consequent expression of TF mRNA and TF activity. We also studied the inhibition of these effects of LPS by rBPI23, a 23-kD recombinant fragment of bactericidal/permeability increasing protein, which has been shown to antagonize LPS in vitro and in vivo. Human peripheral blood mononuclear cells, or monocytes isolated by adherence, were stimulated with Escherichia coli O113 LPS at physiologically relevant concentrations (> or = 10 pg/mL). The effect of LPS was dependent on the presence of the serum protein LBP (lipopolysaccharide-binding protein), as shown by the potentiating effect of human recombinant LBP or serum. Furthermore, recognition of low amounts of LPS by monocytes was also dependent on CD14 receptors, because monoclonal antibodies against CD14 greatly reduced the LPS sensitivity of monocytes in the presence of serum or rLBP. Induction of TF activity and mRNA expression by LPS were inhibited by rBPI23. The expression of tumor necrosis factor showed qualitatively similar changes. Considering the involvement of LPS-induced TF in the potentially lethal intravascular coagulation in sepsis, inhibition of TF induction by rBPI23 may be of therapeutic benefit.
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PMID:Monocyte tissue factor induction by lipopolysaccharide (LPS): dependence on LPS-binding protein and CD14, and inhibition by a recombinant fragment of bactericidal/permeability-increasing protein. 751 3

Marked elevation of transforming growth factor-beta 1 (TGF-beta 1) has been demonstrated clinically following injury and in sepsis. While alterations in the monocyte binding site (CD14) for the lipopolysaccharide (LPS)-lipopolysaccharide binding protein (LBP) complex have been noted with exposure to LPS, immune complexes, gamma-interferon, and IL-4, it is not known whether TGF-beta 1 can alter CD14 expression. To study the effect of TGF-beta 1 on monocyte CD14 expression, human leukocytes were isolated from healthy donors with discontinuous gradient centrifugation and incubated at 37 degrees C for 2 and 24 hr with increasing doses of purified human platelet TGF-beta 1. Monocytes were immunofluorescently stained with monoclonal antibodies recognizing CD14 and CD16. The cells were analyzed by flow cytometry. At 2 hr, 50 ng/ml TGF-beta 1 significantly lowered CD14 expression (51%, P = 0.043). At 24 hr, there was no significant difference between cells stimulated by TGF-beta 1 and control cells. To confirm that TGF-beta 1 was active at 24 hr, we examined levels of CD16. CD16 expression was increased by 10 ng/ml of TGF-beta 1. These observations suggest that high physiologic concentrations of TGF-beta 1 cause early monocyte suppression of CD14. Thus, CD14 may be marker for the transition of monocytes to macrophages and TGF-beta 1 may be responsible for the down-regulation of CD14 expression observed in monocytes obtained from septic patients.
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PMID:Transforming growth factor-beta 1 lowers the CD14 content of monocytes. 752 45

The gastrointestinal tract, besides being the organ responsible for nutrient absorption, is also a metabolic and immunological system, functioning as an effective barrier against endotoxin and bacteria in the intestinal lumen. The passage of viable bacteria from the gastrointestinal tract through the epithelial mucosa is called bacterial translocation. Equally important may be the passage of bacterial endotoxin through the mucosal barrier. This article reviews the evidence that translocation of both endotoxin and bacteria is of clinical significance. It summarises recent published works indicating that translocation of endotoxin in minute amounts is a physiological important phenomenon to boost the reticuloendothelial system (RES), especially the Kupffer cells, in the liver. Breakdown of both the mucosal barrier and the RES capacity results in systemic endotoxaemia. Systemic endotoxaemia results in organ dysfunction, impairs the mucosal barrier, the clotting system, the immune system, and depresses Kupffer cell function. If natural defence mechanisms such as lipopolysaccharide binding protein, high density lipoprotein, in combination with the RES, do not respond properly, dysfunction of the gut barrier results in bacterial translocation. Extensive work on bacterial translocation has been performed in animal models and occurs notably in haemorrhagic shock, thermal injury, protein malnutrition, endotoxaemia, trauma, and intestinal obstruction. It is difficult to extrapolate these results to humans and its clinical significance is not clear. The available data show that the resultant infection remains important in the development of sepsis, especially in the critically ill patient. Uncontrolled infection is, however, neither necessary nor sufficient to account for the development of multiple organ failure. A more plausible sequelae is that bacterial translocation is a later phenomenon of multiple organ failure, and not its initiator. It is hypothesized that multiple organ failure is more probably triggered by the combination of tissue damage and systemic endotoxaemia. Endotoxaemia, as seen in trauma patients especially during the first 24 hours, in combination with tissue elicits a systemic inflammation, called Schwartzmann reaction. Interferon gamma, a T cell produced cytokine, is thought to play a pivotal part in the pathogenesis of this reaction. This reaction might occur only if the endotoxin induced cytokines like tumour necrosis factor and interleukin 1, act on target cells prepared by interferon gamma. After exposure to interferon gamma target cells become more sensitive to stimuli like endotoxin, thus boosting the inflammatory cycle. Clearly, following this line of reasoning, minor tissue damage or retroperitoneal haematoma combined with systemic endotoxaemia could elicit this reaction. The clinically observed failure of multiple organ systems might thus be explained by the interaction of tissue necrosis and high concentrations of endotoxin because of translocation. Future therapeutic strategies could therefore focus more on binding endotoxin in the gut before the triggering event, for example before major surgery. Such a strategy could be combined with the start of early enteral feeding, which has been shown in animal studies to have a beneficial effect on intestinal mucosal barrier function and in traumatized patients to reduce the incidence of septic complications.
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PMID:Clinical significance of translocation. 812 86

A chimeric protein consisting of the N-terminal domain of lipopolysaccharide-binding protein and the C-terminal domain of bactericidal/permeability-increasing protein demonstrated a dose-dependent survival benefit (P = 0.001) and reduced endotoxin levels (P < 0.01) in neutropenic rats with Pseudomonas aeruginosa sepsis. This lipopolysaccharide-binding protein-bactericidal/ permeability-increasing peptide has favorable pharmacokinetics and antiendotoxin properties which may be of value for human sepsis.
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PMID:Activity of lipopolysaccharide-binding protein-bactericidal/permeability-increasing protein fusion peptide in an experimental model of Pseudomonas sepsis. 859 28

Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) are major mediators of sepsis and multiple organ failure. Serum-mediated macrophage activation requires lipopolysaccharide (LPS) and its serum binding protein, lipopolysaccharide binding protein as a ligand for the receptor CD14. This study was designed to determine whether cytokines participate in regulation of serum-mediated LPS activation. Rat macrophages were stimulated with LPS with and-without TNF-alpha or IL-1 beta and activation was determined by detection of TNF-alpha by specific enzyme-linked immunosorbent assay or TNF-alpha mRNA by Northern blot analysis. The addition of TNF-alpha but not IL-1 beta, in the presence of serum, leads to potentiation of macrophage activation after LPS stimulation. This effect could be specifically inhibited by neutralization of LPS with polymyxin B or an antibody against TNF-alpha. This study shows that LPS and TNF-alpha synergize to potentiate serum-mediated macrophage activation. These results demonstrate another element of the control mechanism of cytokine secretion following macrophage activation in sepsis.
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PMID:Lipopolysaccharide and tumor necrosis factor-alpha synergy potentiate serum-dependent responses of rat macrophages. 879 55

The identification of lipopolysaccharide binding protein (LBP) and CD14 as key molecules in the cellular response to endotoxin has been a major advance in unravelling the pathophysiological basis of Gram-negative sepsis. Much interest has focused on developing effective anti-endotoxin treatments to abrogate the inflammatory consequences of Gram-negative infection. The therapeutic options can be divided into those aimed at neutralizing or clearing circulating endotoxin, including anti-endotoxin antibodies and endotoxin neutralizing proteins, and those that antagonize the effects of endotoxin on human cells--for example, lipid A analogues. Initial experiences with anti-lipopolysaccharide antibodies have been disappointing but a new generation of anti-endotoxin agents is about to enter clinical trials. Whether these will prove sufficiently effective to reduce the morbidity and mortality of Gram-negative sepsis remains to be seen.
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PMID:Anti-endotoxin therapeutic options for the treatment of sepsis. 951 Oct 89


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